Hepatitis C Virus (HCV) infection is a major cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma. The World Health Organization estimates that approximately 3% of the world population, or 170 million people, have been infected with the Hepatitis C virus. In the United States, an estimated 3.9 million Americans have been infected with HCV (CDC fact sheet September 2000). Over 80% of HCV-infected individuals develop chronic hepatitis, which is associated with disease states ranging from asymptomatic carrier states to repeated inflammation of the liver and serious chronic liver disease. Over the course of 20 years, more than 20% of chronic HCV-patients are expected to be at risk to develop cirrhosis or progress to hepatocellular carcinoma. Liver failure from chronic hepatitis C is the leading indicator for liver transplantation. Excluding transplantation, the CDC estimates that medical and work-loss cost for HCV annually are around $600 million.
HCV is transmitted primarily by blood and blood products. Due to routine screening of the blood supplies from mid-1992, new transfusion-related cases are exceedingly rare and have been surpassed by injection drug use as the highest risk factor for acquiring the virus. There is also a sexual, however inefficient, route of transmission, and a 6% rate of transmission from infected mothers to their children, which is higher in case of HIV co-infection. In a certain percentage of infections, the mode of transmission remains unknown. In spite of the significant decline in incidence in the 1990's, the number of deaths (estimated deaths annually at the moment: 8000 to 10,000 in U.S.) and of severe disease due to HCV is anticipated to triple in the next 10 to 20 years. (Sources: CDC fact sheets, accessed Dec. 12, 2000; Houghton, “Hepatitis C Viruses”, in Fields Virology, B. N. Fields, D. M. Knipe, P. M. Howley, eds. (Lippencott-Raven Pub., Philadelphia, (1996); Rosen and Gretch, Molecular Medicine Today, 5: 393 (September 1999); Science, 285: 26 (July 1999): News Focus: The scientific challenge of Hepatitis C; Wong et al., Am J Public Health, 90: 1562 (October 2000), estimating future hepatitis C morbidity, mortality, and costs in the United States.)
According to the announcement from the EASL (European Association for the Study of the Liver) International Consensus Conference on Hepatitis C (Feb. 26-28, 1999, Paris, France), combination therapy of alpha interferon and ribavirin is the recommended treatment for naive patients. Monotherapy with interferon has also been approved by the FDA, but the sustained response rate (i.e., HCV RNA remains undetectable in the serum for more than 6 months after end of therapy) is only 15 to 20%, in contrast to 35 to 45% with combination therapy. Interferons (Intron A, Schering-Plough; Roferon A, Hoffmann-LaRoche; Wellferon, Glaxo Wellcome; Infergen, Amgen) are injected subcutaneously three times a week, ribavirin (Rebetol, Schering-Plough) is an oral drug given twice a day. Recommended treatment duration is 6 to 12 months, depending on HCV genotype. Experimental forms of slow-release pegylated interferons (Pegasys, Hoffmann-LaRoche; PEG-Intron, Schering-Plough) have shown improvements in response rates (42 to 82% in combination with ribavirin) and application (once-weekly injection) in recent clinical studies (Hepatology 32:4, Pt 2 of 2. October 2000; NEJM 343, 1673. December 2000; NEJM 343, 1666. December 2000). Common side effects of interferon therapy include: e.g., fatigue, muscle aches, head aches, nausea, fever, weight loss, irritability, depression, bone marrow suppression, reversible hair loss. The most common side effects of ribavirin are anemia, fatigue and irritability, itching, skin rash, nasal stuffiness, sinusitis, cough. More serious side effects of mono-and combination therapy occur in less than two percent of patients (NIDDK information: Chronic Hepatitis C: Current Disease Management; accessed Sep. 12, 1999). Some of the contraindications to interferon are psychosis or severe depression; neutropenia and/or thrombocytopenia; organ transplantation except liver; symptomatic heart disease; decompensated cirrhosis; uncontrolled seizures. Contraindications to ribavirin are end-stage renal failure; anemia; hemoglobinopathies; severe heart disease; pregnancy; no reliable method of contraception (consensus statement EASL). Moreover, treatment of Hepatitis C virus infection with interferon-alpha is effective in only a minority of individuals. This suggests that the virus may be resistant to interferon.
Moreover, although the combination therapy of interferon and ribavirin induces a sustained virologic response in up to 50 to 60% of cases, a significant number of patients do not respond to the combination therapy. (See, Hoofnagle J H, di Bisceglie A M, N. Engl. J Med. 1 336(5): 347-356 (1997)).
Other experimental treatments include: the administration of Maxamine (histamine dihydrochloride, Maxim Pharmaceuticals), which will be combined with Interferon in phase III studies; VX-497 (Vertex Pharmaceuticals), an IMP dehydrogenase inhibitor, as a less toxic ribavirin substitute in phase II; and amantadine (Endo Labs), an approved influenza drug, as the third component in triple therapy (phase II). Inhibitors for HCV enzymes such as protease inhibitors, RNA polymerase inhibitors, helicase inhibitors as well as ribozymes and antisense RNAs are under preclinical development (Boehringer Ingelheim, Ribozyme Pharmaceuticals, Vertex Pharmaceuticals, Schering-Plough, Hoffmann-LaRoche, Immusol, Merck, etc.). No vaccine is available for prevention or therapeutic use, but several companies are trying to develop conventional or DNA vaccines or immunostimulatory agents (e.g., Chiron, Merck/Vical, Epimmune, NABI, Innogenetics).
In addition, antibodies against HCV virion have been developed and entered into clinical trials recently (Trimera Co., Israel).
In summary, the available treatment for chronic Hepatitis C is expensive, effective only in a certain percentage of patients, and commonly leads to adverse side effects.
What is needed, therefore, is an alternate and effective approach to inhibiting HCV replication and for treating HCV infections in patients, particularly in patients who fail to respond to current therapies involving interferon.